Comparison of haplo-SCT and chemotherapy for young adults with standard-risk Ph-negative acute lymphoblastic leukemia in CR1.

Abstract Human leukocyte antigen (HLA) haploidentical stem cell transplantation (haplo-SCT) as a postremission treatment for standard risk Philadelphia chromosome-negative acute lymphoblastic leukemia (SR Ph-ALL) in the first complete remission (CR1) has not been defined. In this multicenter, phase 3 study (NCT02042690), of the 131 consecutive Ph-ALL young adult patients (YA, aged 18–39 years) without high-risk features who achieved CR1, 114 patients without HLA-matched donors received consolidation with an adult chemotherapy regimen (n = 55) or haplo-SCT (n = 59). In the landmark analysis, haplo-SCT resulted in a lower 2-year cumulative incidence of relapse (CIR, 12.8% vs 46.7%, P = 0.0017) and superior 2-year leukemia-free survival (LFS, 80.9% vs 51.1%, P = 0.0116) and 2-year overall survival (OS, 91.2% vs 75.7 [64.8–93.2] %, P = 0.0408) than chemotherapy. In the time-dependent multivariate analysis with propensity score adjustment, postremission treatment (haplo-SCT vs chemotherapy) was an independent risk factor for the CIR (HR 0.195, 95% CI 0.076–0.499, P = 0.001), LFS (HR 0.297, 95% CI 0.131–0.675, P = 0.003), and OS (HR 0.346, 95% CI 0.140–0.853, P = 0.011). In all subgroups, CIR was lower in haplo-SCT. Myeloablative haplo-SCT with ATG+G-CSF might be one of the preferred therapies for YA patients with standard-risk Ph-ALL. Trial registration ClinicalTrials.gov. Registered on 23 January 2014, https://clinicaltrials.gov/ct2/show/NCT02042690


To the Editor:
Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-ALL) is categorized as high risk (HR) with risk factors such as advanced age, elevated WBC count, and high-risk cytogenetic abnormalities.
The remaining older adolescents and young adults (AYA, aged 15-39 years) without risk factors are AYA with standard-risk (SR) Ph-ALL and represent a group with lower cumulative incidence of relapse and better overall survival. Allogeneic hematopoietic stem cell transplantation (allo-SCT), especially from human leukocyte antigen (HLA)-matched sibling donors (MSDs) or matched unrelated donors (MUDs), is one of the preferred options over chemotherapy in the consolidation treatment of Ph-ALL [1,2]. However, the shortage of MSDs and limited availability of MUDs prevents large populations from benefiting from allo-SCT [3].
In total, 131 consecutive Ph-ALL young adult patients (YA, aged 18-39 years) without high-risk features who achieved CR1 were enrolled with a median follow-up of 32 months ( Figure S1, Table S1). haplo-SCT was superior to chemotherapy in terms of lower CIR and improved LFS and OS in total enrolled CR1 patients without landmark ( Figure S2); haplo-SCT was also associated with lower CIR and improved LFS in the subgroup of patients who took only 1 cycle to achieve CR and been MRD negative after Con-1 ( Figure S3).
Dynamic landmark suggested haplo-SCT was associated with lower CIR and improved LFS and OS compared with chemotherapy between 0 and 12 months post-CR1( Figure S4). Then, 6 months was chosen as the fixed landmark point, relapse or NRM before 6 months post-CR1 (n = 15) was excluded, those undergoing SCT after the landmark were included in the chemotherapy group, and the remaining patients (n = 99) were divided into the haplo-SCT group (n = 49) and chemotherapy group (n = 50) ( ; P = 0.0408) continued to be better in the haplo-SCT group than in the chemotherapy group (Fig. 1a, c, d), while NRM was comparable (Fig. 1b).
Cox PH regression model was constructed considering the time of haplo-SCT as a time-dependent exposure based on PH test (Table S3). Univariate analysis for CIR,  No independent risk factors identified for NRM. When stratified by Con-1 MRD and diagnosis, haplo-SCT decreased CIR in all subgroups (Con-1 MRD+ vs MRD−, B-ALL vs T-ALL) while improved LFS and OS only in the Con-1 MRD+ and B-ALL subgroups but not in the Con-1 MRD− and T-ALL subgroups (Table S5, Fig. 2). Currently, haplo-SCT is only an optional rather than a preferred choice for postremission therapy compared with MSD or 10/10 MUD-SCT MSD-SCT is the preferred treatment for ALL, and MUD is also acceptable in most countries [7]. This study presents the first prospective assessment related to the controversial issue whether YA patients with SR ALL benefit more from haplo-SCT than adult chemotherapy regimen. The advantages of a low CIR and an acceptable NRM resulted in promising results of haplo-SCT in the present study, which were comparable to those in previous reports (5-year LFS 68.7%, OS 70.1%) [5,8]. As NRM of haplo-SCT has generally improved with either the PT-CY (7 to 23%) or ATG+G-CSF protocol (11-13%) compared with early procedures [4,9,10], NRM might no longer be a limiting factor of receiving haplo-SCT, especially in experienced centers. haplo-SCT was associated with lower CIR in both the Con-1 MRD +/− subgroups in the current study; meanwhile, cautions must be taken as CIR of non-SCT cohort might be higher compared with previous reports (46-49%) [1,2]. More recently, some studies suggested pediatric-inspired regimens might further decrease the CIR to 12-33% and result encouraging survival (3-5 years LFS 59-73%, OS 60-79%) compared with adult regimen [11], while some reported similar outcomes [12]. Currently, guidelines tried to recommend the regimens both by adult and pediatric settings as adult regimens were still widely used, especially in developing countries [13,14]. In addition, blinatumomab, which might further decrease CIR in MRD+ALL [15], was not available in the current study. Therefore, it remained to be addressed the role of haplo-SCT in the era of pediatric-inspired regimens and blinatumomab in the future.
The present study might be one of the best available evidence to compare haplo-SCT and adult chemotherapy for YA SR Ph-ALL in CR1. Cautions must be taken in interpreting these results due to non-randomized design and a relatively small group of patients. haplo-SCT might become one of the preferred therapies for YA patients with SR Ph-ALL in the absence of MSD or MUD-SCT.